The long-term goal of this research project is to improve the efficacy of anti-nicotine vaccination/immunotherapy for smoking cessation. The proposal relates to the special interest of NIDA in RFA- OD-09-004: "Nicotine and Tobacco Research" and addresses the specific area, "Vaccines/Immunotherapies for Substance Related Disorders." Nicotine dependence, maintained by tobacco smoking, is a chronic relapsing disorder that constitutes one of the leading preventable causes of death in developed countries. In the United States, where approximately 47 million adults are current cigarette smokers, smoking-attributable health care expenditures and productivity losses exceed $190 billion annually. Smoking is extremely addictive, and the efficacy of the available smoking cessation treatments is very low. Compared with traditional pharmacotherapies for nicotine dependence, which substitute and/or modify some of the neuropharmacological effects of nicotine, anti- nicotine immunotherapy is a relatively new approach that directly targets the pharmacokinetics of nicotine. Preliminary studies of human smokers have demonstrated that anti-nicotine vaccination is safe and that this form of immunotherapy could have utility in aiding smoking cessation;however, the efficacy of currently available anti-nicotine vaccinations does not exceed that of traditional pharmacotherapies. Improvements of anti-nicotine immunotherapies require knowledge of precisely how anti-nicotine antibodies affect the pharmacokinetics of nicotine during cigarette smoking. On the basis of our analysis of the relevant published findings along with our preliminary PET data on the pharmacokinetics of nicotine in non-vaccinated smokers, who received the radiotracer 11C-nicotine in cigarette smoke, we propose a new model of how anti-nicotine antibodies affect nicotine pharmacokinetics and how they may facilitate smoking cessation. In contrast to the currently prevailing hypothesis, we hypothesize that success in smoking cessation after anti-nicotine vaccination is associated with the reduction of brain nicotine accumulation after the first puffs as well as during smoking of an entire cigarette. Even though the antibodies are nearly saturated by nicotine after passing through the lungs, they will lose bound nicotine when passing through the peripheral tissues, which have relatively low blood perfusion. Such "recycling" can allow the antibodies to bind nicotine in the lungs again and thereby to prevent nicotine accumulation in the brain following subsequent cigarette puffs. To verify this hypothesis, we propose to study nicotine pharmacokinetics before and after anti-nicotine vaccination in 65 smokers. We will assess nicotine pharmacokinetics during and after the smoking of cigarettes containing 11C-nicotine using PET, consistent with our previously established protocol. We will monitor changes in the extent of nicotine dependence and in the rate of smoking behavior after immunization, and correlate these changes with alterations in nicotine pharmacokinetics. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading preventable cause of disease and death in the U.S. This health burden can be reduced substantially by quitting smoking, and yet current smoking cessation treatments have limited effectiveness. By advancing the vaccine/immunotherapy, which is a highly promising treatment approach, this project has the potential to have a major positive impact on public health.